Sub-additive (antagonistic) interaction of lacosamide with lamotrigine and valproate in the maximal electroshock-induced seizure model in mice: an isobolographic analysis

Abstract

Background Launching polytherapy with two or three antiseizure drugs (ASDs) in patients with epilepsy is still problematic. The choice of ASDs to combine them together is usually based on clinicians’ experience and it requires knowledge about mechanisms of action of the studied ASDs and their drug–drug interactions, whose nature may be favorable, neutral or unfavorable. To characterize three-drug interaction among lacosamide (LCM), lamotrigine (LTG) and valproate (VPA), the type I isobolographic analysis was used. The antiseizure effects of three-drug combination were analyzed in a model of maximal electroshock-induced seizures (MES) in albino Swiss mice. Materials and methods The seizure activity in mice was evoked by alternating current stimulation (25 mA, 500 V, 50 Hz, 0.2 s). Both, the type I isobolographic analysis and the test of parallelism of dose-response effects of the ASDs were used so as to properly classify interaction among three ASDs, administered in a fixed ratio combination of 1:1:1. Results The three-drug mixture of LCM, LTG and VPA at the fixed ratio of 1:1:1 protected the experimental mice from MES-induced seizures; however, the reported interaction was sub-additive (antagonistic; p < 0.01) with isobolography. Conclusion The antagonistic pharmacodynamic interaction among LCM, LTG and VPA in the MES test in mice cannot be transferred to clinical settings and this unfavorable combination should not be recommended for patients with epilepsy.

Three-drug combination of lacosamide, phenobarbital and valproate exerts additive interaction in the tonic-clonic seizure model in mice

“…On the other hand, some three-drug combinations comprising LCM occurred antagonistic (i.e., LCM+CBZ+VPA and LCM+LTG+VPA) in the mouse tonic-clonic seizure model (Tab. 2) [9,10]. At present, it is not clear why some combinations of three AEDs produce additivity while the others exert antagonistic interaction.…”

“…LCM might be combined with PB and VPA for patients with refractory epilepsy uncontrolled with monotherapy. [33] OXC + PGB + TPM supra-additivity [11] PB + PHT + PGB supra-additivity [34] LCM + CBZ + LTG additivity [31] LCM + CBZ + PB additivity [30] LCM + LTG + PB additivity [32] CBZ + PB + VPA additivity [35] LCM + LTG + VPA sub-additivity [9] LCM + CBZ + VPA sub-additivity [10] CBZ -carbamazepine; LCM -lacosamide; LTG -lamotrigine; OXC -oxcarbazepine; PB -phenobarbital; PGB -pregabalin; PHT -phenytoin; TPM -topiramate; VPA -valproate.…”

“…Only VPA (sodium salt -Sigma-Aldrich, Poznań, Poland) was dissolved in sterile distilled water. The drugs were injected intraperitoneally: LCM at 15 min, PB -at 60 min and VPA -at 30 min, before the electrically-evoked tonic-clonic seizures, as described elsewhere [9,14,15].…”

“…The aim of this study was to determine the exact type of interaction among three AEDs: lacosamide (LCM), phenobarbital (PB), and valproate (VPA) by means of isobolographic analysis of interaction, as recommended elsewhere [9,10,12]. Due to various molecular mechanisms of action of the studied AEDs, the three-drug combination of LCM+PB+VPA should theoretically exert supra-additivity (synergy) in the mouse tonic-clonic seizure model.…”

“…Accumulating experimental evidence indicates that some triple combinations of AEDs may produce not only synergistic, additive, but also antagonistic interaction [9][10][11]. There is no doubt that only AEDs in combinations exerting synergistic and additive interactions, can be recommended for patients with refractory epilepsy [5].…”